ABSTRACT
Rationale There are few treatment options for severe COVID-19 pneumonia. Opaganib is an oral treatment under investigation. Objective Evaluate opaganib treatment in hospitalized patients with severe COVID-19 pneumonia. Methods A randomized, placebo-controlled, double-blind phase 2/3 trial was conducted in 60 sites worldwide from August 2020 to July 2021. Patients received either opaganib (n=230; 500mg twice daily) or matching placebo (n=233) for 14 days. Main Outcome Measurements Primary outcome was the proportion of patients no longer requiring supplemental oxygen by day 14. Secondary outcomes included changes in the World Health Organization Ordinal Scale for Clinical Improvement, viral clearance, intubation, and mortality at 28- and 42-days. Main Results Pre-specified primary and secondary outcome analyses did not demonstrate statistically significant benefit (except for time to viral clearance). Post-hoc analysis revealed the fraction of inspired oxygen (FiO2) at baseline was prognostic for opaganib treatment responsiveness and corresponded to disease severity markers. Patients with FiO2 levels at or below the median value ([≤]60%) had better outcomes after opaganib treatment (n=117) compared to placebo (n=134). The proportion of patients with [≤]60% FIO2 at baseline that no longer required supplemental oxygen (at least 24 hours) by day 14 of opaganib treatment increased (76.9% vs 63.4%: p-value =0.033). There was a 62.6% reduction in intubation/mechanical ventilation (6.84% vs 17.91%; p-value=0.012) and a clinically meaningful 62% reduction in mortality (5.98% vs 16.7%; p-value=0.019) by day 42. No new safety concerns observed. Conclusions Post-hoc analysis supports opaganib benefit in COVID-19 severe pneumonia patients that require lower supplemental oxygen ([≤]60% FiO2). Further studies are warranted.
Subject(s)
COVID-19 , Pneumonia , Severe Acute Respiratory SyndromeABSTRACT
Objective The objective of this feasibility study was to assess the number of patients that could be included in a future Real World Evidence study, which would be designed to explore the impact of Paxlovid (nirmatrelvir/ritonavir) on patient outcomes and healthcare resource utilization (HCRU). We also intend to assess the comparability of the patients who were treated with Paxlovid versus patients who did not receive the treatment, either because they declined any COVID-19 treatment or were diagnosed with COVID-19 prior to Paxlovid availability. Methods This retrospective observational secondary data study used data from the Maccabi Healthcare Services database during the identification period of June 1, 2021, to February 28, 2022. The study population included patients with at least one positive SARS-CoV-2 RT-PCR test, or a formal rapid antigen test for SARS-CoV-2, during the identification period, the date of which also served as the COVID-19 diagnosis date. We then divided the study population into the following cohorts: Pre-Paxlovid Time Period and Paxlovid Time Period, which was further split into Paxlovid Treated and Paxlovid Untreated. Results Application of inclusion and exclusion criteria to the study population rendered 20,284 patients in the Pre-Paxlovid Time Period cohort and 5,542 in the Paxlovid Time Period cohort that were eligible to receive Paxlovid. This resulted in 3,714 in the Paxlovid Treated and 1,810 in the Paxlovid Untreated cohorts. Conclusions This RWE feasibility study of patients with a positive test for COVID-19 between June 1, 2021 to February 28, 2022 illustrates potential comparability between cohorts, as described by their demographics and characteristics.
Subject(s)
COVID-19ABSTRACT
Importance: Waning immunity against COVID-19 in parallel with an increased incidence during the Omicron outbreak led the Israeli Ministry of Health to recommend a second booster dose of BNT162b2 (Pfizer) to high-risk individuals. Israel was the first country to recommend this, allowing evaluation of the added protection of a fourth vaccine dose to hospitalized patients with severe diseases. Objective: To assess the effect of a fourth dose for hospitalized patients with severe/critical breakthrough COVID-19. Design: A cohort study of hospitalized adults from 01/15/2022-01/31/2022. Settings: A multi center study of 14 medical centers in Israel. Participants: Hospitalized adult patients with PCR-confirmed severe/critical COVID-19. Excluded were patients lacking data on vaccination status. Exposure: Cases were divided according to the total number of vaccine doses received up to 7 days before diagnosis. Unvaccinated adults and single-dose recipients were grouped into an unvaccinated group. Main Outcome: A composite of mechanical ventilation or in-hospital death was defined as poor outcome. Outcomes were compared between 3- and 4-dose vaccinees. Results: Included were 1,049 patients with severe/critical COVID-19, median age 80 (IQR 69-87), 51% males. Among them, 360 unvaccinated, 34, 172, 386 and 88 were after 1, 2, 3 or 4 doses, respectively. Patients after 3 doses were older, had more males and immunosuppression, but with similar outcomes, 49% vs. 51% compared to unvaccinated patients (p=0.72). Patients after 4 doses were similarly older and immunosuppressed, but had improved outcomes compared to unvaccinated patients, 34% vs. 51% (p<0.01). We proceeded to examine independent predictors for poor outcome in fully-vaccinated patients with either 3 doses given a median of 161 (IQR 147-168) days earlier, or 4 doses given a median of 14 (IQR 10-18) days before diagnoses. Receipt of the fourth dose conferred significant protection: OR 0.51 (95%CI 0.30.87). Conclusion and Relevance: Within a population of hospitalized patients with severe/critical breakthrough COVID-19, a recent fourth dose was associated with significant protection against mechanical ventilation or death, compared to fully-vaccinated single boosted individuals.
Subject(s)
COVID-19 , DeathABSTRACT
The duration of protection of the third (booster) dose of the BioNTech/Pfizer BNT162b2 mRNA Coronavirus Disease 2019 vaccine has yet to be sufficiently researched, while global discussions around the necessity and effectiveness of a fourth dose are already underway. By conducting a retrospective study implementing a test-negative case-control design, analyzing 546,924 PCR tests performed throughout January 2022 by 389,265 persons who received three doses of the vaccine, we found that the effectiveness in each month since vaccination decreased significantly. Compared to those vaccinated early, on August 2021, relative protection against infection waned from 53.4% a month after vaccination to 16.5% three months after vaccination. These results suggest that there is a significant waning of vaccine effectiveness against the Omicron variant of the third dose of the BNT162b2 vaccine within a few months after administration and should prompt policy discussion as to additional booster doses and vaccine development.
Subject(s)
COVID-19ABSTRACT
Introduction: The hallmarks of pulmonary derangement due to severe COVID-19 disease include hypoxemia and a dysregulated and excessive immune response, i.e. a "cytokine storm". Several case series reported on the beneficial effect of hyperbaric oxygen therapy (HBOT) on COVID-19 patients. The aim of the current study was to evaluate the effects of HBOT on COVID-19 patients using a prospective randomized controlled design.Methods: Thirty-one severe COVID-19 inpatients, suffering from respiratory insufficiency in addition to at least one other risk factor, were randomized to HBOT or a control arms in a 2:1 ratio. Patients underwent baseline evaluations which included symptoms questionnaire, vital signs and blood tests. The HBOT arm patients underwent eight HBOT sessions twice daily. The evaluation was repeated on day 5, the day after the last HBOT session.Results: Compared to the control group, one day following the last HBOT session, there was a significant increase in room air saturation in the HBOT patients (F=15·269, p=0·001), significant improvement in the NEWS severity score (F=16·379, p=0·001) and a decreased respiratory rate (F=15·269, p=0·001). There was a significant decrease in CRP and LDH in the HBOT group compared to the control group (CRP: F=5·322, p=0·032, LDH: F=5·599, p=0·027) and a significantly higher proportion developed COVID-19 IgG antibodies compared to the control group (p<0·001).Conclusion: This study demonstrates, for the first time in a prospective randomized clinical trial, that HBOT is a safe therapeutic modality that can improve oxygenation, attenuate inflammation and improve the clinical status of severely ill COVID-19 patients. Larger scale studies are needed to evaluate the effect on inpatient mortality.Trial Registration: The study was registered at clinicaltrials.gov NCT04358926.Funding Statement: The study was supported by the research fund of ShamirMedical Center. Declaration of Interests: Amir Hadanny, Yair Bechor, Yonatan Zemel work for AVIV ScientificLTD., Shai Efrati is a shareholder at AVIV Scientific LTD., all other authors have nothing to disclose. Ethics Approval Statement: This study was approved by the Institutional Review Board (IRB) at Shamir Medical Center and the Israeli National Review Board.
Subject(s)
COVID-19 , Hypoxia , Respiratory InsufficiencyABSTRACT
Coronavirus disease 2019 (COVID-19) exerts deleterious effects on the cardiorespiratory system, leading to worse prognosis in the most effected. The aim of this retrospective multi-center study was to describe the variability of key cardiopulmonary vitals amongst hospitalized COVID-19 patients, measured every 15 minutes using a novel wearable chest-monitor. A total of 492 patients were included, with >3 million measurements collected including heart rate, systolic and diastolic blood pressure, cardiac output, cardiac index, systemic vascular resistance, respiratory rate, blood oxygen saturation, and body temperature. We show differential trajectories of these vital signs, apparent within the first 24hrs of monitoring. Importantly, we show for the first time that cardiovascular deterioration appears early after admission and in parallel with changes in the respiratory parameters, and identify sub-populations at high risk. Combining frequent monitoring using wearable technology with advanced big data and AI analysis tools may aid early detection of deterioration of COVID-19 patients.
Subject(s)
COVID-19 , Coronavirus Infections , Cardiovascular DiseasesABSTRACT
Background: Identifying hospitalized patients with Coronavirus disease 2019 (COVID-19) in a low prevalence setting is challenging. We aimed to identify differences between COVID-19 positive and negative patients. Methods: Hospitalized patients with respiratory illness, or fever, were isolated in the emergency room and tested for COVID-19. Patients with a negative PCR and low probability for COVID-19 were taken out of isolation. Patients with a higher probability for COVID-19 remained in isolation during hospitalization and were retested after 48 hours. Risk factors for COVID-19 were assessed using logistic regression. Results: 254 patients were included, 37 COVID-19-positive (14.6%) and 217 COVID-19-negative (85.4%). Median age was 76 years, 52% were males. In a multivariate regression model, variables significantly associated with COVID-19 positivity were exposure to a confirmed COVID-19 case, length of symptoms before testing, bilateral and peripheral infiltrates in chest X-ray, neutrophil count within the normal range, and elevated LDH. In an analysis including only patients with pneumonia (N=78, 18 positive for COVID-19), only bilateral and peripheral infiltrates, normal neutrophil count and elevated LDH were associated with COVID-19 positivity. Conclusions: The clinical presentation of COVID-19 positive and negative patients is similar, but radiographic and laboratory features may help to identify COVID-19 positive patients and to initiate quick decisions regarding isolation.